title: A small-animal pharmacokinetic/pharmacodynamic PET study of central serotonin 1A receptor occupancy by a potential therapeutic agent for overactive bladder.
abstract: Serotonin 1A (5-HT1A) receptors have been mechanistically implicated in micturition control, and there has been a need for an appropriate biomarker surrogating the potency of a provisional drug acting on this receptor system for developing a new therapeutic approach to overactive bladder (OAB). Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET) imaging, and assessed the utility of a receptor occupancy (RO) assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50) estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%). Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co, Ltd., Tsukuba, Ibaraki, Japan ; Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Chiba, Japan ; Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nakatani
authors.forename: Michiyuki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Masaki
authors.initials: M
authors.lastname: Tokunaga
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Miyuki
authors.initials: M
authors.lastname: Sakai
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ishihara
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshinaga
authors.forename: Osamu
authors.initials: O
authors.lastname: Takenaka
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D003198:Computer Simulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects; D013477:Superior Colliculi / Q000187:drug effects; D013997:Time Factors; D053201:Urinary Bladder, Overactive / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000503:physiopathology; D014554:Urination / Q000187:drug effects
chemical_list: D010880:Piperidines; D044282:Receptor, Serotonin, 5-HT1A; C032727:piperidine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin